K-Ras in cancer metabolism

Researchers from the Dana-Farber Cancer Institute have
identified two glucose metabolism pathways that are activated by the K-Ras oncogene
in pancreatic tumors.1 Based on the findings, it may be possible to
target proteins in the pathways to block proliferation of K-Ras-driven cancers.

Tumors
typically grow and proliferate by dramatically increasing their rate of
glycolysis compared with that in normal cells. Cancers rely on the process,
called the Warburg effect, because it supplies energy and intermediates to
sustain tumor growth. Thus, blocking glycolysis and potentially other metabolic
pathways in tumors could cut off the malignancy's energy and nutrient supply.

Now,
Alec Kimmelman and colleagues at Dana-Farber have shown that the K-Ras oncogene
upregulates two glucose metabolism pathways in pancreatic tumors. The team also
identified enzymes in each of the pathways that could become new therapeutic
targets for pancreatic cancer.

K-Ras mutations are best
known as drivers of resistance to epidermal growth factor receptor (EGFR) inhibitors. Activating mutations in
K-Ras are found in more than 90% of patients with pancreatic
cancer. Although the gene is a driver for cancer initiation and progression,
there are no disclosed small molecule inhibitors selective for mutant K-Ras in development
because attempts to target the complex biology and interactions of the mutant
form of the protein have been unsuccessful.

Prior work had shown that mutant K-Ras drives tumor growth in part by
hijacking metabolic pathways in tumors. Those results suggested it might be
possible to block the effects of K-Ras by going downstream and targeting
proteins in a protumorigenic metabolic pathway. The challenge was identifying
which metabolic pathways mutant K-Ras
hijacked.

To
find those pathways, the Dana-Farber team designed a mouse model of pancreatic
ductal adenocarcinoma (PDAC) that expressed K-ras in the pancreas only in the
presence of doxycycline. To further increase the number of pancreatic lesions
that progressed to PDAC, the team also knocked out the tumor suppressor p53.

Finally,
the team showed that treatment of the K-ras-mutant tumors with a MEK inhibitor downregulated the same set
of metabolism genes. However, treatment with inhibitors of mammalian target of rapamycin (mTOR; FRAP; RAFT1) or the PI3K and AKT pathway did not
reduce gene expression.

Those
findings suggest the MEK pathway downstream of K-Ras is the relevant mechanism
that promotes cancer metabolism in pancreatic tumors, whereas other pathways
such as the PI3K and mTOR pathway do not affect cancer metabolism.

"The
fact that many oncogenic or tumor suppressor pathways have an impact on cell
metabolism has been one of the key factors underpinning the recent resurgence
in cancer metabolism research," said Neil Jones, senior principal target
validation scientist at Cancer Research UK's Cancer Research Technology Ltd. commercial arm.

Cancer Research Technology and AstraZeneca plc
are identifying cancer metabolism targets and developing therapeutics against
them under a three-year deal.

"The
research area of cancer metabolism is undergoing a renaissance driven by a
greater understanding of how genetic drivers reprogram metabolic pathways,"
added Patrick O'Connor, VP and head of oncology at Ruga Corp. The company has multiple preclinical
programs focused on tumor-selective adaptive responses including tumor
metabolism.

"Because
it is difficult to inhibit the Ras oncogene directly,
this paper provides a number of downstream mediators that could become
alternative therapeutic targets for Ras-driven tumors. The goal is to engineer
potent and selective inhibitors impacting various points in the pathways
uncovered in this manuscript as a step toward therapeutic intervention in the
clinic," said O'Connor.

Based
on the new findings, GFPT1 "could be a potential target, as glycosylation
is an intriguing area of cancer research, with this post-translational
modification playing a fundamental role in many tumor-related responses
including proliferation, invasion, immune response and angiogenesis,"
added Jones.

O'Connor said the findings should also encourage "further
preclinical investigation of MEK inhibition with inhibitors of glucose uptake
or inhibitors of glucose utilization through the various pathways identified."

Next steps

Kimmelman told SciBX his team is
performing further mechanistic studies on the key pathways elucidated in the
paper and is designing inhibitors of the newly identified targets.

Jones
said a key area of investigation "would be to evaluate the role of
different K-Ras mutations in tumor metabolism. There is
evidence that different K-Ras mutants utilize
different effector pathways that could give rise to an alternative metabolic
phenotype."

"It
will also be important to evaluate the expression and significance of some of
the identified targets in clinical samples of K-Ras-dependent prostate cancers
to see if the identified metabolism enzyme signature translates into clinical
samples," said Jones.

He
said it also will be necessary to study "potential bypass mechanisms of
alternative metabolic pathways and any toxicity implication in rapidly
proliferating normal tissues."

Finally,
because the potential cancer metabolism targets described in the paper were
identified primarily through genetic studies, a key next step will be to
determine whether selective and potent pharmacologic inhibitors of these
reprogrammed pathways can safely reproduce the same results, said O'Connor.

Kimmelman
said Dana-Farber has filed a patent application covering the findings and the
new targets. The IP is available for licensing.

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